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Synthesis, methods of using, and compositions of cycloalkylmethylamines

a technology of cycloalkylmethylamine and synthesis method, which is applied in the field of cycloalkylmethylamines, synthesis of cycloalkylmethylamines, can solve the problems of limited advances in the pharmacotherapy of this condition, increased risk of alzheimer's-type dementia, and increased risk of certain types of cancer, etc., to achieve favorable metabolic, pharmacokinetic and pharmacological profiles, and high pharmacokinetic profiles

Active Publication Date: 2011-08-02
REVIVA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]The compounds of the subject invention provide next generation noradrenergic and serotonergic active appetite suppressants, and are particularly effective and safe for the treatment of obesity and co-morbid diseases and / or disorders. They are advantageous because of their favorable metabolic, pharmacokinetics and pharmacological profiles. Specifically, these compounds are primarily metabolized by hydrolytic enzymes not by cytochrome P450 enzymes. These compounds have a highly predictable pharmacokinetic profile and are particularly advantageous because their metabolites have reduced systemic exposure in comparison to the active drug.

Problems solved by technology

Obesity can cause a number of health problems either directly or indirectly, such as, for example, type 2 diabetes, coronary heart disease, high blood triglycerides, high blood pressure and stroke.
Obesity also raises risk of certain types of cancer.
Death from some cancers may be more likely because obesity makes the cancers harder to detect in the early stages (for example, the initial small lump of breast cancer may not be felt in an obese woman).
Recent studies show obesity increases the risk of Alzheimer's-type dementia.
Despite the seeming inexorable progression of this disease, there have been limited advances in the pharmacotherapy of this condition.
The only thermogenic drug combination that has been tested is ephedrine and caffeine, but this treatment has not been approved by regulatory agencies.
This is one of the major limitations of this drug for the long term use in the treatment of obesity.
However, sibutramine's therapeutic use for the treatment of obesity, and other diseases and disorders is currently not fully utilized because of certain limitations and adverse side effects associated with the drug.
The major adverse events reported, in some cases life threatening, include increase in blood pressure and the side effects derived from the drug-drug interactions, for example, serotonin syndrome.

Method used

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  • Synthesis, methods of using, and compositions of cycloalkylmethylamines
  • Synthesis, methods of using, and compositions of cycloalkylmethylamines
  • Synthesis, methods of using, and compositions of cycloalkylmethylamines

Examples

Experimental program
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example 1

General Procedure for Synthesis of 49a-d (Scheme 7)

[0189]The phenylcyclobutanenitriles 49a-d were prepared according to the protocol reported by Butler and Polatz (J. Org. Chem. 1971, 36, 1308). To a stirred suspension of sodium hydride (NaH) (0.1 mole, 2.4 g) in 25 mL of anhydrous tetrahydrofuran (THF) under nitrogen atmosphere at ice-bath temperature was dropwise added a solution of 1,3-dibromopropane (11.10 g, 0.055 mole) and appropriate benzylnitrile 47a-d (0.05 mole) in 50 mL of THF. The resulting mixture was slowly warmed to room temperature and continued stirring overnight (12 hours) at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction was poured onto crushed ice (200 g) and then, extracted with ethyl acetate (100 mL×3). The combined extract was washed with water (100 mL×2), dried over magnesium sulfate (MgSO4) and evaporated under reduced pressure to give the corresponding phenylcyclobutanenitriles 49a-d which were ...

example 2

General Procedure for Synthesis of 52a-d (Scheme 7)

[0194]To a stirred solution of 2M isobutyl magnesium bromide in diethyl ether (0.04 mole, 20 mL) under nitrogen atmosphere at room temperature was dropwise added a solution of appropriate cyclobutanenitrile 49a-d (0.025 mole) in 20 mL of anhydrous THF or toluene. The resulting mixture was refluxed for 18-24 hours. The progress of the reaction was monitored by TLC. In a separate round bottom flask 25 mL of anhydrous isopropanol was taken and sodium borohydride (3.00 g, 0.08 mole) was added to isopropanol portion-wise at room temperature. After having stirred for 10 minutes, the Grignard adduct from the reaction flask was directly added into the stirred solution sodium borohydride in isopropanol under nitrogen atmosphere. The resulting mixture was refluxed for 12 to 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was slowly poured onto a mixture of crushed ice (200 g) and sodium bicarbonate (5.00 g). ...

example 3

General Procedure for Synthesis of 54a-e (Scheme 7)

[0200]To a stirred suspension of cesium carbonate (Cs2CO3) (1.30 g, 0.004 Mole) in 20 mL of anhydrous N,N-dimethylformamide (DMF) under nitrogen atmosphere at room temperature was added tetrabutylammonium iodide (TBAI) (1.47 g, 0.004 mole) followed by appropriate cyclobutane amine 52a-d (0.0035 mole). After having stirred for 30 minutes, a solution of appropriate bromoalkylcarboxylic esters 53 in 5 mL of DMF was introduced into the reaction mixture dropwise. The resulting mixture was stirred for 18-24 hours and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), filtered through a CELITE® pad and washed the CELITE® pad with ethyl acetate (15 mL×3). The combined filtrate was washed with brine (50 mL), water (50 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography technique using 0-50% gradient of ethyl acetate a...

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Abstract

The present invention provides novel cycloalkylmethylamine analogs, and methods of preparing cycloalkylmethylamine analogs. The present invention also provides methods of using cycloalkylmethylamine analogs and compositions of cycloalkylmethylamine analogs. The pharmaceutical compositions of the compounds of the present invention can be advantageously used for treating and / or preventing obesity and obesity related co-morbid indications.

Description

CROSS REFERENCE OF RELATED APPLICATIONS[0001]The present application claims the benefit of U.S. Provisional Application Ser. No. 60 / 825,868, filed on Sep. 15, 2006, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to cycloalkylmethylamines, synthesis of cycloalkylmethylamines and methods of using cycloalkylmethylamines for the pharmacological treatment of obesity and obesity related co-morbid indications.BACKGROUND OF THE INVENTION[0003]Obesity is a chronic disease that affects millions of people across the world especially in the developed countries. It is defined by excess body fat and is generally measured by calculating a person's BMI (body mass index). If a person's BMI is 30 or above, he or she considered to be obese. Obesity can cause a number of health problems either directly or indirectly, such as, for example, type 2 diabetes, coronary heart disease, high blood triglycerides, high blood pressure and stroke...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/135C07C211/00
CPCC07C229/14C07C271/16C07C229/34C07C2101/04C07C2601/04A61P1/00A61P1/04A61P1/08A61P13/00A61P15/00A61P15/08A61P15/10A61P19/02A61P25/00A61P25/04A61P25/06A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P25/36A61P3/04A61P7/00A61P7/02A61P7/12
Inventor BHAT, LAXMINARAYANBHAT, SEEMA RANI
Owner REVIVA PHARMA INC
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